The opioid crisis highlights the urgent need for novel non-addictive pain medications, as well as improved treatments for opioid addiction and overdose. There is a need for pharmacological agents directed at novel targets to test new therapeutic hypotheses, new clinic-ready drugs directed at those targets, and new testing systems with the potential to be more predictive of human clinical response than traditionally used models. Therefore, a key human-based screening technology for the discovery of novel therapeutics for the opioid crisis will be iPSC technology, which allows the generation of human sensory neurons and other cell types relevant to pain, addiction, and overdose. The NCATS Stem Cell Translation Laboratory (SCTL) has developed a scalable and fully automated protocol to generate pure cultures of sensory neurons (nociceptors) in large quantities under chemically defined conditions. The available screening capabilities, scalable production of the most relevant human cell types, and their real-time functional characterization provide unprecedented opportunities to, in collaboration with external pain/addiction experts, to identify probe/lead compounds with improved predictivity for in vivo human effects. In addition, Disease-in-a-dish iPSC-derived models utilizing iPSCs from patients with pain or addictive disorders may advance understanding of different types of pain, and differences in individual pain responses or risk of developing chronic pain or addiction upon opioid exposure.